CN112047831B - Monobutylketone crystallization process, single crystal and culture method thereof - Google Patents
Monobutylketone crystallization process, single crystal and culture method thereof Download PDFInfo
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- CN112047831B CN112047831B CN202011097045.7A CN202011097045A CN112047831B CN 112047831 B CN112047831 B CN 112047831B CN 202011097045 A CN202011097045 A CN 202011097045A CN 112047831 B CN112047831 B CN 112047831B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
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- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B29/00—Single crystals or homogeneous polycrystalline material with defined structure characterised by the material or by their shape
- C30B29/54—Organic compounds
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- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
- C30B7/08—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions by cooling of the solution
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
A method for crystallizing menthone and a monocrystal and a culture method thereof, wherein the method for crystallizing menthone comprises the following steps: adding solvent into the crude product of the menthone, heating and stirring, dissolving, adding active carbon, maintaining the temperature and stirring for 30 minutes, filtering while the active carbon is hot, standing and cooling the filtrate to 5-10 ℃, filtering and drying to obtain white crystalline powder; the invention discloses a single crystal culture method of menthone, which comprises the following steps: adding the menthone powder with the purity of 99 percent into a solvent, heating and dissolving, then cooling to 5-10 ℃, standing for one week, and separating out crystals; the invention focuses on researching that the product meets the requirement of injection by crystallization; the crystallization solvent can be recycled, so that the solvent is saved, three wastes are reduced, and the cost is greatly reduced; the absolute configuration of the crystal form of the menthone and the Meng Bu ketone molecule is determined by the single crystal culture, and the compound of the crystal form is prepared into powder, so that the invention has remarkable advantages in the aspects of bioavailability and the like.
Description
Technical Field
The invention relates to the field of veterinary medicines, in particular to a process for crystallizing menthone, a single crystal and a culture method thereof.
Background
Meng Bu ketone is 3- (4-methoxynaphthoyl) propionic acid, is easy to dissolve in acetone, is dissolved in chloroform, is slightly soluble in methanol and ethanol, is slightly soluble in diethyl ether, is almost insoluble in water, is easy to dissolve in sodium hydroxide solution, is Meng Bu ketone raw material and preparation, is approved to be marketed in Germany as early as 1965, is approved by European veterinary drug product Commission as an animal-specific cholagogue in 1996, and can promote secretion of bile, gastric juice and pancreatic juice. Thereby increasing the supply of cholate, pepsin, trypsin, pancreatic amylase, pancreatic lipase and the like, effectively treating animal dyspepsia, inappetence, constipation, abdominal distention and other gastrointestinal dysfunction, improving digestion and absorption functions, and being applicable to the dyspepsia of cattle, sheep, goats, pigs, horses, dogs and the like; the composition has mild and safe effects, has no obvious adverse effects on the central nervous system, the cardiovascular system, the respiratory system, the urinary system, the digestive system and the reproductive system, has no effect on uterine smooth muscle of female animals, does not cause reproduction disadvantage and abortion, can be used for pregnant animals, and has wide application prospect in veterinary clinic; up to now, the preparation of menthone is marketed in the countries of germany, france, uk, italy, switzerland etc.; meng Bu ketone bulk drugs, injection and powder are just approved as new veterinary drugs in 2020, but the product does not enter the market yet, so the bulk drugs will necessarily be very popular in the future.
Patent CN104370734a discloses a method for synthesizing menthone, which discloses that crude menthone is coarsely crystallized by using water as solvent, and decolorized by active carbon to obtain refined menthone;
document Demethylation of a methoxy group during the synthesis of- (4-methoxy-1-nanoyl) propionic acid (menbutone) in the Friedel-crafts reaction in the presence of aluminium chloride as a catalyst, hura, bogum et al (2003), 47 (3), 147-154 mentions that the crude product is recrystallized from acetone;
the disadvantages of the prior art are: 1) The properties of the composition do not meet the requirements of solutions; 2) The dosage of the acetone is large, the national management and control of the solvent easy to poison is strong in volatility, the crystallization is easy in the filtering process, and the control is not good; and the yield is not high.
Disclosure of Invention
The purpose of the invention is that: overcomes the defects of the prior art and provides a process for crystallizing the menthone, a monocrystal and a culture method thereof.
The invention adopts the technical scheme that:
the invention provides a crystallization method of menthone, which comprises the following steps:
adding solvent into the crude product of the menthone, heating and stirring, dissolving, adding active carbon, maintaining the temperature and stirring for 30 minutes, filtering while the active carbon is hot, standing and cooling the filtrate to 5-10 ℃, filtering and drying to obtain white crystalline powder; the solvent is methanol, ethanol, acetic acid, tetrahydrofuran or DMF.
More preferably, in the crystallization method, the solvent is methanol.
More preferably, in the crystallization method, the dosage ratio of the crude product of the menthone to the solvent is 1g:15-30ml. More preferably, the dosage ratio is: 1g:20-25ml.
More preferably, in the above crystallization method, the temperature of the heating dissolution is 60 to 80 ℃ and is not more than the boiling point of the solvent.
The invention also provides a single crystal cultivation method of the montelukast ketone, which comprises the following steps: adding the menthone powder with the purity of 99 percent into a solvent, heating and dissolving, then cooling to 5-10 ℃, standing for one week, and separating out crystals; the solvent is methanol, ethanol, isopropanol, acetic acid, ethyl acetate, acetone or chloroform tetrahydrofuran.
Preferably, in the single crystal cultivation method, the ratio of the amount of the menthone powder to the amount of the solvent is: 1g:30ml.
Preferably, in the above single crystal growing method, the heating dissolution temperature is 45-80 ℃ and is not more than the boiling point of the solvent.
Preferably, in the above single crystal growing method, the solvent is methanol.
The invention also provides a Monobutyronine crystal, which belongs to monoclinic system, C2/C space group, purity is more than 99%, unit cell parameter isα＝90°,β＝96.172(9)°,γ＝90°,/>
The invention has the beneficial effects that:
1) The invention mainly researches the crystallization process of the crude drug of Meng Bu ketone, and the crude drug sold by a plurality of factories in the market of the crude drug at present is grey and white, so that the requirement of injection cannot be met; therefore, the invention focuses on researching that the product meets the requirement of injection through crystallization (the crystalline powder is prepared into a preparation, and the property meets the requirement of the color standard of the No. 1 preparation); the crystallization solvent can be recycled, so that the solvent is saved, three wastes are reduced, and the cost is greatly reduced;
2) The absolute configuration of the crystal form of the menthone and the Meng Bu ketone molecule is determined by the single crystal culture, and the compound of the crystal form is prepared into powder, so that the invention has remarkable advantages in the aspects of bioavailability and the like.
Drawings
FIG. 1 shows the structural formula of Meng Bu ketone.
FIG. 2 is a molecular steric configuration of a single crystal of Monobutylketone.
Fig. 3 is a graph comparing the pharmacokinetic curves of single crystal powder of montelukast and Meng Bu ketone powder.
Detailed Description
The invention is further illustrated below with reference to specific examples, but without limiting the scope of the invention.
Example 1
A crystallization method of menthone, comprising the steps of:
10g of crude product of the menthone is taken and added into a 500ml three-neck flask, 220ml of methanol is added, the mixture is heated to boiling, stirred and dissolved, then 1g of active carbon is added, stirring is carried out for 30 minutes at a maintained temperature, the mixture is filtered while the mixture is still hot, the filtrate is placed at 10-15 ℃ and cooled for 30 minutes, the filtrate is filtered and dried, and 8.8 g of white crystalline powder is obtained, and the yield is 88%.
Example 2
A crystallization method of menthone, comprising the steps of:
10g of crude product of the menthone is taken and added into a 500ml three-neck flask, 250ml of methanol is added, the mixture is heated to boiling, stirred and dissolved, then 1g of active carbon is added, stirring is carried out for 30 minutes at a maintained temperature, the mixture is filtered while the mixture is still hot, the filtrate is placed at 10-15 ℃ and cooled for 30 minutes, the filtrate is filtered and dried, and 8.2 g of white crystalline powder is obtained, and the yield is 82%.
Example 3
A crystallization method of menthone, comprising the steps of:
10g of crude product of the menthone is taken and added into a 500ml three-neck flask, 300ml of ethanol is added, heating and stirring are carried out, 70 ℃ is adopted for dissolution, then 1g of active carbon is added, stirring is carried out for 30 minutes at a maintained temperature, filtering is carried out while the active carbon is still hot, the filtrate is placed at 10-15 ℃ for cooling for 30 minutes, filtering is carried out, and drying is carried out, thus obtaining 65 g of white crystalline powder with the yield of 65%.
Example 4
A crystallization method of menthone, comprising the steps of:
10g of crude product of the menthone is taken and added into a 250ml three-neck flask, 150ml of acetic acid is added, heating and stirring are carried out, 80 ℃ is adopted for dissolution, then 1g of active carbon is added, stirring is carried out for 30 minutes at a maintained temperature, filtering is carried out while the active carbon is still hot, the filtrate is placed at 10-15 ℃ for cooling for 30 minutes, filtering and drying are carried out, and 7.5 g of white crystalline powder is obtained, and the yield is 75%.
Comparative example 1
A crystallization method of menthone, comprising the steps of:
taking 10g of a crude product of the menthone, adding the 10g into a 500ml three-neck flask, adding 300ml of acetone, heating and stirring, dissolving at 60 ℃, then adding 1g of active carbon, stirring for 30 minutes at a maintained temperature, filtering while the mixture is hot, standing the filtrate at 10-15 ℃ for cooling for 30 minutes, filtering, and drying to obtain 6.1 g of white crystalline powder with the yield of 61%;
example 5
A single crystal cultivation method of menthone, comprising the steps of:
1.0g of a powder of 99% purity of menthone was added to 30ml of methanol, and the mixture was dissolved by heating at 50℃and allowed to stand still for one week to precipitate crystals. Selecting single crystals with the size of 0.22mm by 0.18mm by 0.06mm, and collecting derivative data by using a Bruker Smart ApexII CCD derivative instrument;
description of Crystal Structure
The crystal belongs to monoclinic system, the purity is more than 99% and the unit cell parameters are as follows:
TABLE 1
Example 6 pharmacokinetic profile comparison of Monobutylketone Single Crystal powder and Monobutylketone powder for single administration
1 Material
1.1 pharmaceutical products
Test article: monobutylketone single crystal powder (Meng Bu ketone raw material is single crystal type, crystal form structure is shown in table 1), content specification is 10%, and the Monobutylketone single crystal powder is provided by Tianjin City challenge biotechnology Co.
Control: mono-crystalline powder of Mono-crystalline powder (Meng Bu ketone raw material used is common powder raw material) with a content specification of 10% is provided by the lifting challenge biotechnology Co., ltd.
The usage amount is as follows: calculated as menthone. Oral administration: the weight of the pig is 10-30 mg for every 1kg of body weight. Mixing with feed, and administering orally.
1.2 test animals
Healthy long white X big white hybrid pigs, which have a weight of about 50kg and are male and female. Is provided by a Tianjin city Zitianyi farm. The test pigs are marked by earmarks. The subject animals were not used with the relevant drug for at least 2 weeks prior to the test and had undergone an adaptation period of at least 1 week. The tested animals are fed according to the conventional conditions during the test period, drink water and eat freely, and the feed is a complete feed without any medicine.
2 method
2.1 Experimental design and dosing regimen
The 16 pigs were randomly divided into 2 groups A and B, each group being 8. Before the test, the test is carried out according to the conventional feeding, free drinking and feeding, the feed is full-price daily ration (without antibacterial drugs), and the test is observed for two weeks. After clinical observation of health, the test was performed.
Parallel test designs were used. The 16 pigs with similar weight are randomly divided into 2 groups, wherein the first group of pigs No. 1-8 are orally taken with single dose of the Monobutylketone powder, and the second group of pigs No. 9-16 are orally taken with the Monobutylketone single crystal powder. The administration method comprises the following steps: orally taking 20mg/kg bw (equivalent to a dosage of about 10g for each pig by singly taking), and mixing the test product into feed for natural feeding.
2.2 blood sample collection and preservation
Animals were weighed and blood was collected via the anterior vena cava. Blank blood was collected one day prior to dosing (at 0 f), and blood samples were collected 15, 30min and 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h (1 d) each once after dosing. The blood sampling amount is about 2-4mL each time, the blood sample is placed into a 10mL centrifuge tube which is soaked by heparin and dried at 60 ℃, and after uniform mixing, the blood sample is centrifuged, and the blood plasma is separated and stored in a refrigerator at-20 ℃ for standby.
2.3 determination of the content of Montanone in plasma samples
After the plasma samples collected at each time point are treated, the content of the montelukast in the plasma samples at each time point is calculated by adopting a verified HPLC method for measuring the content of the Meng Bu ketone in the pig plasma to obtain the peak area of the montelukast, and a following standard curve regression equation is used for calculating the content of the montelukast in the plasma samples at each time point.
2.4 data analysis
The measured plasma drug concentration-time data are analyzed by Winnolin 5.2 pharmacokinetic software, and t of the oral administration of the two preparations is calculated respectively 1/2 、AUC、C max And T max And (3) drawing a blood concentration distribution curve according to the pharmacokinetic parameters, comparing the principal pharmacokinetic parameters of the two parameters, and judging whether the significance difference exists or not.
3 results
MontelbufoneOral administration at a dose of 20mg/kg body weight, results of pharmacokinetic studies in pigs showed that the peak concentrations (Cmax) of Monobutyronine single crystal powder and Monobutyronine were 17.21 μg/ml and 17.52 μg/ml, respectively, the Monobutyronine single crystal powder elimination half-life T 1/2 T of Montelukast powder for 6.10h 1/2 For 4.91h, it is demonstrated that the rate of elimination of single crystal powder of menthone is relatively slower than that of menthone powder in the body. Mono-crystalline powder of menthone and the area under the time curve (AUC) of the menthone powder 0→last ) 122.30 h. Mu.g/mL and 102.92 h. Mu.g/mL, respectively, with a relative bioavailability of 118.83%. In summary, the bioavailability of the single crystal powder of the montelukast in pigs is better than that of the montelukast.
Claims (2)
1. A single crystal of montelukast, characterized in that: the single crystal of the montelukast belongs to monoclinic system, the purity is more than 99 percent, and the unit cell parameter is thatα＝90°,β＝96.172(9)°,γ＝90°,/>
2. The method for producing a single crystal of montelukast as claimed in claim 1, wherein: the method comprises the following steps:
1.0g of a powder of 99% purity of menthone was added to 30ml of methanol, and the mixture was dissolved by heating at 50℃and allowed to stand still for one week to precipitate crystals.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL211222B1 (en) * | 2008-04-28 | 2012-04-30 | Inst Przemysłu Organicznego | Method of purification of 3-(4-methoxy-1-naphthoyl) propionic acid |
| CN103417476A (en) * | 2013-08-22 | 2013-12-04 | 西南大学 | Menbutone injection liquid for veterinary use and preparation method thereof |
| CN104370734A (en) * | 2014-11-19 | 2015-02-25 | 西南大学 | Improved synthesis method of menbutone |
| CN107703139A (en) * | 2017-10-20 | 2018-02-16 | 西南大学 | A kind of method for determining veterinary menbutone bulk drug content |
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- 2020-10-14 CN CN202011097045.7A patent/CN112047831B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL211222B1 (en) * | 2008-04-28 | 2012-04-30 | Inst Przemysłu Organicznego | Method of purification of 3-(4-methoxy-1-naphthoyl) propionic acid |
| CN103417476A (en) * | 2013-08-22 | 2013-12-04 | 西南大学 | Menbutone injection liquid for veterinary use and preparation method thereof |
| CN104370734A (en) * | 2014-11-19 | 2015-02-25 | 西南大学 | Improved synthesis method of menbutone |
| CN107703139A (en) * | 2017-10-20 | 2018-02-16 | 西南大学 | A kind of method for determining veterinary menbutone bulk drug content |
Non-Patent Citations (1)
| Title |
|---|
| "Demethylation of a methoxy group during the synthesis of 3-(4-methoxy-1-naphtoyl) propionic acid (menbutone) in the Friedel-crafts reaction in the presence of aluminium chloride as a catalyst";Bogumila HURAS et al.;《Polish Journal of Applied Chemistry》;20031231(第3期);第147-154页 * |
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